This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
The potential utilities of selective cyclooxygenase-2 inhibitors are discussed in the following articles:
1. John Vane, "Towards a better aspirin" in Nature, Vol. 367, pp. 215-216, 1994 PA0 2. Bruno Battistini, Regina Botting and Y. S. Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994. PA0 3. David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995. PA0 4. Don E. Griswold and Jerry L. Adams, "Constitutive Cyclooxygenase (COX-1) and Inducible Cyclooxygenase (COX-2): Rationale for Selective Inhibition and Progress to Date" in Medicinal Research Reviews, Vol. 16, pp. 181-206, 1996. PA0 a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA0 a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA0 administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA0 administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of formula I. PA0 (1) 3-(4-Methylsulfonyl)phenyl-2-pyrrolidin-1-yl-5-trifluoromethylpyridine, PA0 (2) 3-(4-Methylsulfonyl)phenyl-2-piperidin-1-yl-5-trifluoromethylpyridine, PA0 (3) 5-Chloro-3-(4-methylsulfonyl)phenyl-2-piperidin-1-ylpyridine, PA0 (4) 3-(4-Methylsulfonyl)phenyl-2-piperidin-1-ylpyridine, PA0 (5) 3-(4-Methylsulfonyl)phenyl-2-(1,2,3,6-tetrahydropyridinyl)-5-trifluorometh ylpyridine, PA0 (6) 2-(Homopiperidin-1-yl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethylpyridin e, PA0 (7) 3-(4-Methylsulfonyl)phenyl-2-((2S)-2-hydroxymethyl)pyrrolidin-1-yl-5-trifl uoromethylpyridine, PA0 (8) 3-(4-Methylsulfonyl)phenyl-2-((2R)-2-hydroxymethyl)pyrrolidin-1-yl-5-trifl uoromethylpyridine, PA0 (9) 5-Chloro-3-(4-methylsulfonyl)phenyl-2-((2S)-2-hydroxymethyl)pyrrolidin-1-y lpyridine, PA0 (10) 3-(4-Methylsulfonyl)phenyl-2-((2S)-2-methoxymethyl)pyrrolidin-1-yl-5-trifl uoromethylpyridine, PA0 (11) 3-(4-Methylsulfonyl)phenyl-2-((2S)-2-acetoxymethyl)pyrrolidin-1-yl-5-trifl uoromethylpyridine, PA0 (12) 5-Chloro-3-(4-methylsulfonyl)phenyl-2-((2S)-2-methoxymethyl)pyrrolidin-1-y lpyridine, PA0 (13) 3-(4-Methylsulfonyl)phenyl-2-(2-hydroxymethyl)piperidin-1-yl-5-trifluorome thylpyridine, PA0 (14) (-)-3-(4-Methylsulfonyl)phenyl-2-(3-hydroxymethyl)piperidin-1-yl-5-trifluo romethylpyridine, PA0 (15) (+)-3-(4-Methylsulfonyl)phenyl-2-(3-hydroxymethyl)piperidin-1-yl-5-trifluo romethylpyridine, PA0 (16) 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-hydroxymethyl)piperidin-1-ylpyrid ine, PA0 (17) 3-(4-Methylsulfonyl)phenyl-2-(3-hydroxymethyl-3-methyl)piperidin-1-yl-5-tr ifluoromethylpyridine, PA0 (18) 3-(4-Methylsulfonyl)phenyl-2-(3-hydroxymethyl)homopiperidin-1-yl-5-trifluo romethylpyridine, PA0 (19) 3-(4-Methylsulfonyl)phenyl-2-(2-(2-hydroxyethyl))piperidin-1-yl-5-trifluor omethylpyridine, PA0 (20) 3-(4-Methylsulfonyl)phenyl-2-(4-oxo)piperidin-1-yl-5-trifluoromethylpyridi ne, PA0 (21) 3-(4-Methylsulfonyl)phenyl-2-(3-oxo)piperidin-1-yl-5-trifluoromethylpyridi ne, PA0 (22) 3-(4-Methylsulfonyl)phenyl-2-(4-hydroxy)piperidin-1-yl-5-trifluoromethylpy ridine, PA0 (23) 3-(4-Methylsulfonyl)phenyl-2-(3-hydroxy)piperidin-1-yl-5-trifluoromethylpy ridine, PA0 (24) 2-(4,4-Difluoro)piperidin-1-yl-3-(4-methylsulfonyl)phenyl-5-trifluoromethy lpyridine, PA0 (25) 2-(3,3-Difluoro)piperidin-1-yl-3-(4-methylsulfonyl)phenyl-5-trifluoromethy lpyridine, PA0 (26) 2-(4-Fluoro)piperidin-1-yl-3-(4-methylsulfonyl)phenyl-5-trifluoromethylpyr idine, PA0 (27) 3-(4-Methylsulfonyl)phenyl-2-morpholin-4-yl-5-trifluoromethylpyridine, PA0 (28) 3-(4-Methylsulfonyl)phenyl-2-thiomorpholin-4-yl-5-trifluoromethylpyridine, PA0 administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein. PA0 PEG 200/300/400: restricted to 2 mL/kg PA0 Methocel 0.5%-1.0%: 10 mL/kg PA0 Tween 80: 10 mL/kg PA0 Dextrose: 1 mL/kg PA0 Moleculosol 25%: 1 mL/kg PA0 DMSO (dimethylsulfoxide): Restricted to a dose volume of 0.1 mL per animal PA0 PEG 200: Not more than 60% mixed with 40% sterile water--1 mL/kg